The genomic evolution of SARS-

CoV-2

Francois Balloux
Email: f.balloux@ucl.ac.uk
: @BallouxFrancois
Zoonotic pathogens

• Spillovers of zoonotic disease

are frequent
• Ebola: ~23 outbreaks
• MERS: hundreds
• Flu pandemics

• ~250 known symptomatic

zoonotic viruses

• ~450 known symptomatic

zoonotic bacteria

• Likely many more pathogens

with zoonotic potential
Shaw et al. 2019 Molecular Ecology
Are humans a viral sink?

Tan et al. unpublished

 Publicly available viral genomes (NCBI)
Current state of the global genomic surveillance of vertebrate viruses (n=11,645,803)

Tan, van Dorp and Balloux, 2024 Nature E&E, in press; https://www.biorxiv.org/content/10.1101/2023.09.01.555953v2.abstract
 Viral cliques
Taxonomy-agnostic approach for identifying equivalent units of viral diversity
Anthroponotic vs. zoonotic host jumps
Humans gave more viruses to animals than they gave to us.

Tan, van Dorp and Balloux, 2024 Nature E&E, in press; https://www.biorxiv.org/content/10.1101/2023.09.01.555953v2.abstract
Host jump mutation threshold
Adaptation threshold for host jumps decreases for multi-host viruses.

Tan, van Dorp and Balloux, 2024 Nature E&E, in press; https://www.biorxiv.org/content/10.1101/2023.09.01.555953v2.abstract
Gene-specific adaptation
Adaptation signals are gene specific.
Pandemics
Covid-19 pandemic overview

Balloux et al. 2022 Oxford Open Immunology, 3: iqac003

Covid-19 pandemic overview - origins

Balloux et al. 2022 Oxford Open Immunology, 3: iqac003

The Sarbecoviruses – a zoonotic reservoir

SARS-CoV-1

Divergence estimated
as decades ago
1948 to 1982
Boni et al. Nature. 2020.
Wang et al. Vir Evo. 2020.
RaTG13 (~96%)

RmYN02 (~93%)
SARS-CoV-2
Covid-19 pandemic overview - core

Balloux et al. 2022 Oxford Open Immunology, 3: iqac003

Evolution of SARS-CoV-2 into multiple lineages

Balloux et al. 2022 Oxford Open Immunology, 3: iqac003

Emergence of new variants
Critical mutations

Spike protein Major T-cell epitopes

RBD

RBD

Credit: Outbreak.info Milighetti et al. 2023. iScience 16: 106937. doi: 10.1016/j.isci.2023.106937
Covid-19 pandemic overview - aftermath
Known secondary SARS-CoV-2 host (Dec 2022)

Kuchipudi et al. 2023 Nat Ecol Evol.

https://doi.org/10.1038/s41559-023-02082-0
Secondary spillovers into animals

Tan et al. 2022 Nature Comms.

Recurrent mutations in mink / deer

Tan et al. 2022 Nature Comms.

‘Endemicity’
Coronaviruses in UK bats (pilot screen)

Tan et al. 2023 Nature Comms 14: 3322

Predicted (and realized) receptor binding

Tan et al. 2023 Nature Comms 14: 3322

Zoonotic potential of UK bat sarbecovirus
a
RhGB02 can bind human ACE2 and
use it for cell entry in vitro. (a) Entry
of different spike pseudoviruses
expressing viral glycoproteins into
HEK293T cells transfected with ACE2
homologues from different species or
with an ‘empty’ vector. (b) Entry of
b pseudoviruses into different ‘normal’
human cell lines that stably express
lower or physiological levels of hACE2.

Tan et al. 2023 Nature Comms 14: 3322

Surveillance (in an ideal world)

Coordinated genomic surveillance in humans, the environment, and domestic and wild animals is critical to inform policy
development towards an early warning system for detecting outbreaks in humans and animals. AMR, antimicrobial resistance
Kuchipudi et al. 2023 Nat Ecol Evol 7: 956–959. https://doi.org/10.1038/s41559-023-02082-0
Summary

• Identification of zoonotic threats prior to host-jumps would be ideal

• Future pandemics may not be averted by improved zoonotic surveillance,

but better preparation should help (e.g. stockpiling drugs and vaccines)

• Research into zoonoses needs to be performed more responsibly

• Unbiased (meta-)genomic sequencing would be ideal, but obscenely

expensive. Current data is essentially useless for surveillance

• Most concerning pathogens can be flagged, up to a point Predicting the

next outbreak .epidemic is likely not within the realm of science today
Acknowledgments

Marina Zamudio Cedric Tan

Mislav Acman Liam Shaw

Lucy van Dorp

Coronavirus cliques
Viral cliques identified and their
corresponding user-submitted
species names for the
Coronaviridae. Nodes, node
shapes, and edges represent
individual genomes, their
associated host and their
pairwise Mash distances,
respectively. Edges
representing >0.15 Mash
distance were removed
RNA viruses in UK bats – pilot results

• 48 samples (faeces)

• 16 bat species

• Deep RNA sequencing

• Up to 18 virus species /
sample

• 28 high-quality genomes

• Several new virus species

• ~2/3 insect viruses

Tan et al. 2023 BioRxiv
2023.01. 17.524183
Timeline of spillovers in mink and deer
Immunological niche

• Spill over events of

zoonotic coronaviruses
are probably common

• Most lead nowhere

• Recently acquired
lineages likely poor
transmissibility (R0 ~1)

• Many spillover events

might fail because they
land within a region of
the landscape which is
already occupied
Did SARS-CoV-2 fall in an empty niche?

• SARS-CoV-2 possibly fell

in an ‘empty’ region of
the niche

• Cross-immunity between
SC2 and the four endemic
CoVs is low

• Early SARS-CoV-2, likely

had low R0.

• Wuhan outbreak lineage

(R0 ~2.5; now R0 ~5.0)

SARS-CoV-2
What could we test / predict

3. Can we predict future evolution of lineages under the pressure of cross-immunity and vaccine protection…

Vaccine
What could we test / predict

3. Can we make better predictions about which zoonotic pathogen may spread if it jumped in humans (and had
the potential to infect and transmit). Every existing (or made-up) genome can be placed in the space.